We have begun the identification of senescence-associated mRNAs in A plaques from APP/PS1 mice using laser capture microdissection (LCM). Our preliminary results showed that A-associated brain cells express high levels of senescent-associated transcripts p16 mRNA and p21 mRNA. To further examine if A-associated forebrain tissue included other sensecence markers, we dissected A plaques from APP/PS1 mice present in the forebrain by using LCM. We have also selected several differentially expressed senescence-associated candidate mRNAs. Quantitative PCR analysis in RNA from LCM-captured A plaques revealed that Col1a1, Serpine1, and Cdkn2b (p15) mRNAs, but not Igfbp7 mRNA were dramatically upregulated in A plaques from APP/PS1 mice. These results supported the validity of this methodology to successfully isolate A-associated senescent cells and further indicate that the A plaques from APP/PS1 mice are highly correlated with senescence. Senescence was reported in many different cell types and involve in diverse disease processes. Recently, our group reported a set of universal senescence associated genes from several fibroblasts and endothelial cells by diverse senescence inducer (Casella et al., Nucleic Acids Res 2019). We thus examined whether the RNAs differentially expressed in senescent fibroblasts and endothelial cells were also differentially expressed between WT and APP/PS1 mice. Our ongoing work is aiming to identify the AD plaque-specific RNA expression patterns by large-scale RNA sequencing and single-cell RNA sequencing. Additional investigation aims to (1) identify the specific RNA expression patterns in tissue surrounding human A plaques collected by LCM and assayed by RNA sequencing; (2) identify senescence-associated genes in different brain cell types by single-cell RNA-seq analysis in WT and APP/PS1 mice; and (3) analyze the impact of senolytic drugs on AD-associated RNA expression profiles.